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Reduction of Glutamate Uptake into Cerebral Cortex of Developing Rats by the Branched-Chain Alpha-Keto Acids Accumulating in Maple Syrup Urine Disease

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Abstract

In the current study we investigated the effect of the branched-chain alpha-keto acids (BCKA) α-ketoisocaproic (KIC), α-keto-β-methylvaleric (KMV), and α-ketoisovaleric (KIV) acids, which accumulate in maple syrup urine disease (MSUD), on the in vitro uptake of [3H]glutamate by cere-bral cortical slices from rats aged 9, 21, and 60 days of life. We initially observed that glutamate uptake into cerebral cortex of 9- and 21-day-old rats was significantly higher, as compared to that of 60-day-old rats. Furthermore, KIC inhibited this uptake by tissue slices at all ages studied, whereas KMV and KIV produced the same effect only in cortical slices of 21- and 60-day-old rats. Kinetic assays showed that KIC significantly inhibited glutamate uptake in the presence of high glutamate concentrations (50 μM and greater). We also verified that the reduction of glutamate uptake was not due to cellular death, as evidenced by tetrazolium salt and lactate dehydrogenase viability tests of cortical slices in the presence of the BCKA. It is therefore presumed that the reduced glutamate uptake caused by the BCKA accumulating in MSUD may lead to higher extracellular glutamate levels and potentially to excitotoxicity, which may contribute to the neurological dysfunction of the affected individuals.

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Authors and Affiliations

  1. Instituto de Ciências Básicas da Saúde, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil

    Cláudia Funchal, Aline Meyer Rosa, Moacir Wajner, Susana Wofchuk & Regina Pessoa Pureur

  2. Serviço de Genêtica Mêdica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil

    Moacir Wajner

  3. Instituto de Geriatria e Faculdade de Farmácia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brasil

    Susana Wofchuk

Authors
  1. Cláudia Funchal
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  2. Aline Meyer Rosa
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  3. Moacir Wajner
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  4. Susana Wofchuk
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  5. Regina Pessoa Pureur
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Funchal, C., Rosa, A.M., Wajner, M. et al. Reduction of Glutamate Uptake into Cerebral Cortex of Developing Rats by the Branched-Chain Alpha-Keto Acids Accumulating in Maple Syrup Urine Disease. Neurochem Res 29, 747–753 (2004). https://doi.org/10.1023/B:NERE.0000018846.66943.30

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